Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) is a triazole antifungal drug represented by the structure:

Posaconazole is used, for example, to prevent and/or treat invasive fungal infections caused by Candida species, Mucor species, Aspergillus species, Fusarium species, or Coccidioides species in immunocompromised patients and/or in patients where the disease is refractory to other antifungal agents such as amphothericin B, fluconazole, or itraconazole, and/or in patients who do not tolerate these antifungal agents.
One of the important intermediates for the preparation of posaconazole is the compound of formula (II)
wherein both residues Y1 and Y2 are F. In a conceivable synthetic approach towards the compound of formula (II), the quaternary stereo center is generated by an iodo-cyclization, giving the required tetrahydrofuran as a diastereomeric mixture. In this mixture, the molar ratio of cis-isomer relative to the trans-isomer (cis:trans) is in the range of from 85:15 to 95:5, typically about 9:1. However, only the cis-isomer is desired to be transformed to posaconazole. Consequently, an enrichment of the desired cis-isomer or a suitable salt thereof is necessary.
According to the prior art, the diastereomeric mixture comprising, in a solvent, the cis-isomer of formula (II) and the trans-isomer of formula (III)
was converted, in a first step, to a diastereomeric mixture of the respective tosylates of compounds (II) and (III) exhibiting the same cis:trans ratio as the starting mixture, i.e. typically the 9:1 ratio. From this diastereomeric mixture, the cis-isomer had to be separated in a second step via tedious gradient column chromatography on silica gel using large volumes of a mixture of heptane and ethyl acetate. In the context, reference is made to U.S. Pat. No. 5,403,937, EP 0 736 030 A1, and WO 95/17407. However, column chromatography in general and the above-discussed column chromatography processes in particular are not suitable for industrial-scale processes.
Therefore, it was an object of the present invention to provide a new process for the separation of the cis-isomer according to formula (II).
Looking for such simplified and advantageous new process, it was found that most likely, making use of the known diastereomeric mixture of the tosylate of compounds (II) and (III) was not a promising starting point.
Therefore, it was another object of the present invention to provide a new intermediate containing suitable derivatives of the compounds of formula (II) and (III).
Surprisingly, it was found that above-discussed separation of the cis-isomer can be considerably simplified if, based on the diasteromeric mixture containing the compounds of formula (II) and (III), a specific salt is prepared. This specific salt was found to be the HCl salt of the compounds (II) and (III).